ABSTRACT Defective DNA Mismatch repair causes Hereditary Non-Polyposis Colon Cancer and sporadic cancer. DNA mismatch repair suppresses tumors primarily through four mechanisms: (A) repair of base substitution point mutations, such as G/T mismatches (B) repair of frameshift and small insertion-deletion mutations (commonly called MSI), (C) failure to apoptose in response to DNA damage and (D) suppression of promiscuous DNA recombination (commonly called homeologous recombination). Different E. coli MutL homologues (MLH and PMS genes) and MutS homologues (MSH) interact combinatorially to create multiple complexes with different roles in these four mechanisms of tumor suppression. Briefly, mammalian MLH/PMS proteins heterodimerize to form three distinct complexes, MLH1/PMS1, MLH1/PMS2 and MLH1/MLH3, that interact with MSH proteins. My research program focuses on the mechanistic roles of individual MLH/PMS genes and associated factors in suppression of DNA mismatch repair deficient gastrointestinal (GI) tumor initiation and progression. In Aim1 we probe the roles of individual MLH/PMS genes in suppression of homeologous recombination. This aim will provide important insights into a poorly characterized mechanism of GI tumor suppression. In Aim 2 we analyze in depth our novel finding that PMS1 repairs MSI/frameshift mutations. This aim will provide novel insights into the role of this poorly characterized mismatch repair gene in an important mechanism of tumor suppression. In Aim 3 we test whether the gene we recently discovered, TLE6-like, accelerates progression of mismatch repair deficient GI tumors. This aim will provide important insights into the mechanisms of GI tumor progression in vivo. The overall goal of this study is to understand the roles of individual MLH/PMS and associated genes in mechanisms of DNA mismatch repair deficient GI tumor initiation and progression. This goal is significant because only by understanding the contribution of individual genes to these processes in depth can we prioritize targets and develop better approaches to block GI tumor initiation and progression to adenocarcinoma. Our proposal is innovative because it uses novel computational biology methods to analyze GI tumor kinetics, focuses on a poorly characterized mechanism important for GI tumor suppression and tests novel hypotheses for PMS1 and TLE6-like roles in tumor suppression.